Novel substituted sulfoximine compounds

ABSTRACT

The present invention relates to novel heterocyclic compounds of the general formula (I) their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers and polymorphs. The invention also relates to processes for the preparation of the compounds of invention, pharmaceutical compositions containing the compounds and their use as the compounds of the invention belong to the family of NOD-like receptor family (NLR) protein NLRP3 modulators. The present invention thus relates to novel NLRP3 modulators as well as to the use of the novel inhibitor compounds in the treatment of diseases or conditions as well as treatment of disease states mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1β activity and interleukin-18 (IL-18) is implicated.

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic compounds of thegeneral formula (I) their pharmaceutically acceptable salts,pharmaceutically acceptable solvates, enantiomers, diastereomers andpolymorphs. The invention also relates to processes for the preparationof the compounds of invention, pharmaceutical compositions containingthe compounds and their use as the compounds of the invention belong tothe family of NOD-like receptor family (NLR) protein NLRP3 modulators.The present invention thus relates to novel NLRP3 modulators as well asto the use of the novel inhibitor compounds in the treatment of diseasesor conditions as well as treatment of disease states mediated by NLRP3as well as treatment of diseases or conditions in which interleukin 1βactivity and interleukin-18 (IL-18) is implicated.

BACKGROUND OF THE INVENTION

The NOD-like receptor family (NLR) protein NLRP3 is an intracellularsignaling molecule that senses many pathogens, environmental andhost-derived factors. (Wen., et. al., Immunity. 2013; 39:432-441).Activation of NLRP3 leads to binding with apoptosis associatedspeck-like protein containing a CARD (ASC). ASC in turn interacts withthe cysteine protease caspase-1, forming a complex termed theinflammasome. This results in the activation of caspase-1, which cleavesthe pro-inflammatory cytokines IL-1β and IL-18 to their active forms andmediates a type of inflammatory cell death known as pyroptosis. Otherintracellular pattern recognition receptors (PRRs) are also capable offorming inflammasomes. These include other NLR family members such asNLRP1 and NLRC4 and non-NLR PRRs such as the double-stranded DNA (dsDNA)sensors absent in melanoma 2 (AIM2) and interferon, gamma inducibleprotein 16 (IFI16). (Latz, et. al., Nat Rev Immunol. 2013; 13:397-411)NLRP3-dependent IL-1β processing can also be activated by an indirect,non-canonical pathway downstream of caspase-1 (Lamkanfi, et. al., Cell.2014; 157:1013-1022).

Inflammasome components such as NLRP3, ASC and caspase-1 are expressedin immune cells in the liver including Kupffer cells, infiltratingmacrophages, hepatocytes, and hepatic stellate cells. Inflammasomeactivation is dependent on two successive signals. Signal 1 is driven byTLR and IL-1R signaling, includes expression of component proteinsincluding NLRP3, ASC, pro-caspase-1, pro-IL-1β, and pro-IL-18. Signal 2is provided by danger signals (DAMPS) that during NASH development aremainly released by stressed or dying hepatocytes or via a “leaky” gut(PAMPs). This process leads to oligomerization of the inflammasomecomponents and cleavage of pro-caspase-1, leading to the release ofactive pro-inflammatory cytokines.

The NLRP3 inflammasome acts as a key mediator of inflammatory responsesthrough the activation of caspase-1 leading to processing and release ofthe pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18(IL-18). The NLRP3 inflammasome is a component of the inflammatoryprocess and its aberrant activation is pathogenic in inherited disorderssuch as the rare periodic fever syndrome, cryopyrin associated periodicsyndromes (CAPS), Tumor necrosis factor receptor-associated periodicsyndrome (TRAPS) and complex diseases such as multiple sclerosis, type 2diabetes, atherosclerosis, asthma, gouty arthritis, and inflammatorycentral nervous system (CNS) diseases. (Masters, et. al., Annu RevImmunol. 2009; 27:621-668; Strowig, et. al., Nature 2012, 481, 278-286;Guo, et. al., Nat. Med. 2015, 21, 677.)

Inflammation is an essential host response to infection and injury. Theregulation of the pro-inflammatory cytokine interleukin-1β (IL-1β),which is central to host responses to infection, also causes tissueinjury when activated inappropriately. (Dinarello, et. al., Nat. Rev.Drug Discovery 2012, 11, 633-652.) NLRP3 inflammasome activation plays akey role in each of the components including induction ofpro-inflammatory signaling, hepatocellular injury and cell death, andactivation of the hepatic stellate cells (HSC) that are responsible forcollagen deposition and liver fibrosis. In particular, the transitionfrom NAFLD to NASH associates with NLRP3-inflammasome activation and anincreased expression of inflammasome-related components, includingapoptosis-associated speck-like protein containing a carboxy-terminalCARD (ASC), caspase-1 (CASP-1) and pannexin. (Mridha, et. al., Journalof Hepatology, 2017, 66 (5), 1037-1046)

Current treatments for NLRP3 related diseases include biologic agentsthat target IL-1. These are the recombinant IL-1 receptor antagonistAnakinra, the neutralizing IL-1β antibody Canakinumab and the solubledecoy IL-1 receptor Rilonacept.

Published patent applications WO98/32733, WO2001/019390, WO2014/190015,WO2016/123229 disclose certain WO/2016/131098 filed by The University OfQueensland disclosed sulfonylureas derivatives and related compounds asNLRP3 inflammasome inhibitors. WO2017/017469 filed by The University ofManchester, disclosed certain cyclic diarylboron derivatives as NLRP3inflammasome inhibitors for the treatment of diseases or conditions inwhich interleukin 1 β activity is implicated. Some of the recent patentapplications such as WO2017031161, WO2017079352 disclosed certain classof compounds as NLRP3 inhibitors.

We herein disclose novel heterocyclic compounds of general formula (I)which are NLRP3 Modulators for the prevention and treatment of diseasestates mediated by NLRP3 or conditions in which interleukin 1β activityand interleukin-18 (IL-18) are implicated, including inflammation,Cryopyrin-associated periodic syndromes (CAPS), gouty arthritis, type 2diabetes, atherosclerosis, and liver fibrosis. More particularly,embodiments of the present invention are useful as therapeutics in thetreatment of a variety of pathological conditions including (but notlimited to) lymphoma, auto-immune diseases, heteroimmune diseases,inflammatory diseases, cancer, and neurodegenerative diseases orconditions.

SUMMARY OF THE INVENTION

The present invention discloses heterocyclic compounds as defined by thegeneral formula (I) that are NLRP3 modulators for the prevention andtreatment of disease states mediated by NLRP3 as well as treatment ofdiseases or conditions in which interleukin 1β activity andinterleukin-18 (IL-18) are implicated. The compounds of the presentinvention are useful in the treatment of human or animal body, byinhibition of NLRP3. The compounds of this invention are thereforesuitable for the prevention and treatment of disease states mediated byNLRP3.

EMBODIMENT(S) OF THE INVENTION

An embodiment of the present invention provides novel heterocycliccompounds represented by the general formula (I), their tautomericforms, their enantiomers, their diastereoisomers, their stereoisomers,their pharmaceutically acceptable salts and pharmaceutical compositionscontaining them or their mixtures thereof.

In a further embodiment of the present invention is providedpharmaceutical compositions containing compounds of the general formula(I), their tautomeric forms, their enantiomers, their diastereoisomers,their stereoisomers, their pharmaceutically acceptable salts, or theirmixtures in combination with suitable carriers, solvents, diluents andother media normally employed in preparing such compositions.

In a still further embodiment is provided the use of heterocycliccompounds of the present invention as NLRP3 modulators, by administeringa therapeutically effective and non-toxic amount of compounds of generalformula (I) or their pharmaceutically acceptable compositions to themammals.

In a still further embodiment is provided a process for preparing thenovel compounds of the present invention.

DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to the compounds of thegeneral formula (I)

their tautomeric forms, their stereoisomers, their pharmaceuticallyacceptable salts, and pharmaceutical compositions containing themwherein

-   -   ‘A’ is selected from unsubstituted or substituted (C₁-C₆)alkyl,        (C₂-C₆)alkenyl, (C₃-C₆)cycloalkyl, aryl, heteroaryl and        heterocyclyl groups having optionally one or more than one        heteroatoms;    -   R¹ at each occurrence independently represents hydrogen,        halogen, haloalkyl, cyano, optionally substituted groups        selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy,        (C₃-C₆)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl,        mercapto alkyl, sulfur and its oxidized form.

In an embodiment when A represents ring, R¹ may represent one or moresubstituents selected from hydrogen, halogen, haloalkyl, cyano,optionally substituted groups selected from (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, aryl, heteroaryl,heterocyclyl, benzyl, thiol, mercapto alkyl, sulfur and its oxidizedforms, C₁-C₆(thio-alkoxy), bridged or spiro ring system havingoptionally one or more than one heteroatoms;

‘B’ is selected from optionally substituted (C₃-C₆)cycloalkyl, aryl,heteroaryl and heterocyclyl or the following ring system

wherein X, Y, Z at each occurrence is independently selected from C, N,S, SO₂, and O, which may be, wherever possible be optionallysubstituted;

n=0-3

R² at each occurrence independently represents hydrogen, halide, cyano,optionally substituted groups selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy (C₃-C₆)cycloalkyl, benzyl, aryl, heteroaryl,heterocyclyl, thiol, thioalkyl, thio-alkoxy sulfur and its oxidizedforms, bridged or spiro ring system having optionally one or more thanone heteroatoms;

R³ at each occurrence independently represents hydroxyl, halogen, nitro,cyano, optionally substituted groups selected from (C₁-C₁₀)alkyl,(C₁-C₁₀)alkoxy, (C₃-C₁₀)cycloalkyl, (C₂-C₁₀) alkenyl, (C₂-C₁₀)alkynyl,SO₂(C₁-C₆)alkyl, benzyl, aryl, heteroaryl, heterocyclyl, thiol,thioalkyl, thio-alkoxy, (sulfur and its oxidized forms); in anembodiment, R³ and A together with the atom to which they are attachedmay form a optionally substituted 5 to 7 membered heterocyclic ringsystem having optionally one or more than one heteroatoms; ‘m’represents an integer from 1-5;

Each of R₄, R₅, R₆, R₇, R₈, and R₉ at each occurrence are independentlyselected from hydrogen, halogen, cyano, amide, sulphonamide, acyl,hydroxyl, optionally substituted groups selected from (C₁-C₆)alkyl,(C₁-C₆)haloalkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkoxy; Alternatively eachof R₅ and R₆, R₇ and R₈ or R₈ and R₉ wherever possible, together mayform a 4 to 7 membered saturated or partially saturated ring containingfrom 0-2 additional heteroatoms selected from the group consisting of N,O, and S(O)_(p); p=1-2.

When any of above defined group is substituted the substitutions on themmay be selected from hydrogen, hydroxy, cyano, halo, haloalkyl,haloalkyloxy, alkylthio (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₁₀)cycloalkyl, C₁-C₆ alkoxy, —COR₁₀, —CSR₁₀, C(O)OR₁₀, C(O)—R₁₀,—C(O)—NR₁₁R₁₂, —C(S)—NR₁₁R₁₂, —SO₂R₁₀ group, wherein R₁₀ isindependently selected from hydrogen, optionally substituted groupselected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)cycloalkyl, aryl, heteroaryl, heterocyclyl group;

R₁₁ and R₁₂ is independently selected from hydrogen, optionallysubstituted group selected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl orbenzyl group;

In a preferred embodiment, the groups, radicals described above may beselected from:

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyand alkanoyl, means a carbon chain which may further be substituted withan oxygen atom as is well understood by a skilled artisan, which mayfurther be either linear or branched, and combinations thereof, unlessthe carbon chain is defined otherwise. Examples of alkyl group includebut not are limited to methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert.-butyl, pentyl, hexyl etc. Where the specified number ofcarbon atoms permits e.g. from C3-10, the term alkyl also includescycloalkyl groups, and combinations of linear or branched alkyl chainscombined with cycloalkyl structures. When no number of carbon atoms isspecified, C(1-6) is intended.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof, unless the carbon chain is defined otherwise. Examples ofalkenyl include but not limited to vinyl, allyl, isopropenyl, hexenyl,pentenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl etc. Wherethe specified number of carbon atoms permits, e. g., from C5-10, theterm alkenyl also includes cycloalkenyl groups and combinations oflinear, branched and cyclic structures. When no number of carbon atomsis specified, C(2-6) is intended.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl etc. When no number of carbon atoms is specified, isintended.

the “thioalkyl” group used either alone or in combination with otherradicals, denotes an alkyl group, as defined above, attached to a groupof formula —SR′, where R′ represents hydrogen, alkyl or aryl group, e.g.thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which maybe optionally substituted.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable monocyclic or bicyclic or tricyclic ring, any of whichmay be saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin). In a broader perspective,the term carbocycle is intended to include, wherever applicable, thegroups representing cycloalkyl, phenyl and other saturated, partiallysaturated or aromatic residues;

“Cycloalkyl” is the subset of alkyl and means saturated carbocyclic ringhaving a specified number of carbon atoms, preferably 3-6 carbon atoms.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclicunless otherwise stated. Cycloalkyl groups are saturated unless andotherwise stated.

The “alkoxy” refers to the straight or branched chain alkoxides of thenumber of carbon atoms specified.

“Aryl” means a mono- or polycyclic aromatic ring system containingcarbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.

“Heterocyclyl” means a saturated, partially saturated or unsaturatedaromatic or non-aromatic mono, bi or tricyclic radicals, containing oneor more heteroatoms selected from nitrogen, sulfur and oxygen, furtheroptionally including the oxidized forms of sulfur, namely SO & SO₂.Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran,1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine,1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline,tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane,1,3-dithiane, oxathiane, thiomorpholine, etc. The term“heterocycloalkyl” refers to a heterocyclic group as defined aboveconnected to an alkyl group as defined above; “Heteroaryl” means anaromatic or partially aromatic heterocycle that contains at least onering heteroatom selected from O, S and N. Heteroaryls thus includeheteroaryls fused to the other kinds of rings, such as aryls,cycloalkyls, and heterocycles that are not aromatic. Examples ofheteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl,pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl,benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl,dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl,dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl,dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl,quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl,purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl,benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl etc. Forheterocyclyl; and heteroaryl groups, rings and ring systems containingfrom 3-15 carbon atoms are included, forming 1-3 rings.

The term “haloalkyl” means a alkyl structure in which at least onehydrogen is replaced with a halogen atom. In certain embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are all the same as one another.

the “haloalkoxy” group is selected from suitable haloalkyl, as definedabove, directly attached to an oxygen atom, more preferably groupsselected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxyand the like;

In certain other embodiment in which two or more hydrogen atoms arereplaced with halogen atoms, the halogen atoms are not all the same asone another.

“Aryloxyalkyl” means an alkyl radical substituted with aryloxy group asdefined herein.

“Aryloxyaryl” means an aryl radical substituted with aryloxy group asdefined herein.

“Aryloxyheteroaryl” means a heteroaryl radical substituted with aryloxygroup as defined herein.

“Halo/Halogen” refers to fluorine, chlorine, bromine, iodine. Chlorineand fluorine are generally preferred.

Suitable groups and substituents on the groups may be selected fromthose described anywhere in the specification.

The term “substituted,” as used herein, means that any one or morehydrogen on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.

“Pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofthe basic residues. Such conventional non-toxic salts include, but arenot limited to, those derived from inorganic and organic acids selectedfrom 1,2-ethanedisulfonic, 2-acetoxybenzoic, 2-hydroxyethanesulfonic,acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic,citric, edetic, ethane disulfonic, ethane sulfonic, fumaric,glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic,hexylresorcinic, hydrabamic, hydrobromie, hydrochloric, hydroiodide,hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic,-lauryl sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic,nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic,sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluenesulfonic.

The term ‘optional’ or ‘optionally’ means that the subsequent describedevent or circumstance may or may not occur, and the description includesinstances where the event or circumstance occur and instances in whichit does not. For example, optionally substituted alkyl’ means either‘alkyl’ or ‘substituted alkyl’. Further an optionally substituted groupincludes an unsubstituted group.

Unless otherwise stated in the specification, structures depicted hereinare also meant to include compounds which differ only in the presence ofone or more isotopically enriched atoms.

Particularly useful compounds may be selected from but not limited tothe following:

-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzene    sulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzene    sulfonimidamide;-   N′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-4-methylbenzenesulfonimidamide;-   N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;-   N-((2,6-diisopropylphenyl)carbamoyl)-4-methylbenzenesulfonimidamide;-   N-((2,6-diisopropylphenyl)carbamoyl)-4-methyl-N′-(2,2,2-trifluoroethyl)benzenesulfonimidamide;-   N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-N′-(2,2,2-trifluoroethyl)-benzenesulfonimidamide;-   N-((2,6-diisopropylphenyl)carbamoyl)-N′-methoxy-4-methylbenzenesulfonimidamide;-   N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N′-isopropyl-4-methylbenzenesulfonimidamide;-   N-((2,6-diisopropylphenyl)carbamoyl)-N′-isopropyl-4-methylbenzenesulfonimidamide;-   N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N′-methoxy-4-methylbenzenesulfonimidamide;-   N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N′,4-dimethylbenzenesulfonimidamide;-   N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-N′-(1H-pyrazol-5-yl)benzenesulfonimidamide;-   N′-(4-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;-   N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-N′-(pyridin-2-yl)benzenesulfonimidamide;-   4-acetyl-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-nitrobenzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methoxybenzenesulfonimidamide;-   N′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-4-methoxybenzenesulfonimidamide;-   N′-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;-   N-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)(p-tolyl)-16-sulfanylidene)-methanesulfonamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxypyridine-3-sulfonimidamide;-   N′-cyano-3-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;-   4-chloro-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;-   4-bromo-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;-   4-(benzyloxy)-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(trifluoromethyl)-benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-2-sulfonimidamide;-   Ethyl    ((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)(p-tolyl)-λ⁶-sulfaneylidene)-carbamate;-   N-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)-(p-tolyl)-λ⁶-sulfaneylidene)-acetamide;-   N′-carbamoyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(3-hydroxyoxetan-3-yl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide;-   5-bromo-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methoxybenzene-sulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide;-   N′-cyano-2-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methylbenzenesulfonimidamide;-   N′-cyano-3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide-   N′-cyano-3,5-difluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;-   N′-cyano-2,4-difluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(trifluoromethoxy)-benzenesulfonimidamide;-   N′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-phenylmethanesulfonimidamide;-   N-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(3-(2-hydroxypropan-2-yl)phenyl)(oxo)-16-sulfaneylidene)methanesulfonamide;-   N′-cyano-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dimethoxybenzene-sulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methylpyridine-2-sulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methylpyridine-2-sulfonimidamide;-   N′,3-dicyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfo-nimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-3-sulfonimidamide-   N′,4-dicyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-4-sulfonimidamide;-   N′-cyano-3-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)quinoline-8-sulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-morpholinobenzene    sulfonimidamide;-   N-(3-(N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)    phenyl) acetamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-morpholinobenzene    sulfonimidamide;-   N′-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide;-   N′-cyano-2-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)benzenesulfonimidamide;-   N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)pyridine-3-sulfonimidamide;-   N′-cyano-1-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-methanesulfonimidamide;-   1-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonimidamide;-   N′-cyano-3-(2-hydroxypropan-2-yl)-N-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-benzenesulfonimidamide.

or pharmaceutically acceptable salts of any of the compounds above.

Following is a list of abbreviations used in the description of thepreparation of the compounds of the present invention:

bs: broad singlet

CDCl₃: Deuterated chloroform

CHCl₃: Chloroform

d: doublet

dd: doublet of doublet

dt: doublet of triplet

DCM: Dichloromethane

DMAC: N,N-(Dimethylacetamide)

DMAP: 4-(Dimethylamino) pyridine

DMF: N,N-Dimethyl formamide

DMSO: Dimethyl sulfoxide

EDTA: Ethylenediaminetertraacetic acid

EtOAc: Ethyl acetate

EtOH: Ethanol

HCl(g): Hydrogen chloride (gas)

K₂CO₃: Potassium carbonate

MeOH: Methanol

m: multiplet

mmol: millimoles

μg: microgram

MS: Mass spectrum

Na₂CO₃: Sodium carbonate

ng: nanogram

MS: N-iodosuccinimide

¹H NMR: Proton nuclear magnetic resonance

POCI₃: Phosphorylchloride

s: singlet

t: Triplet

td: triplet of doublet

THF: Tetrahydrofuran

TLC: Thin layer chromatography

RT: room temperature

N₂: Nitrogen

PMA=Phorbol 12-myristate 13-acetate

IL1β: Interleukin 1 beta

TNF α: Tumor necrosis factor alpha

DAMP: damage-associated molecular pattern;

PAMP: pathogen-associated molecular pattern;

TLR: Toll-like receptor.

General Process for Preparation

The novel compounds of the present invention can be prepared using thereactions and techniques described below, together with conventionaltechniques known to those skilled in the art of organic synthesis, orvariations thereon as appreciated by those skilled in the art.

The reactions can be performed in solvents appropriate to the reagentsand materials employed and suitable for the transformations beingaffected. Preferred methods include, but not limited to those describedbelow, where all symbols are as defined earlier unless and otherwisedefined below.

The compounds of the general formula (I) can be prepared as described inschemes below along with suitable modifications/variations which arewell within the scope of a person skilled in the art.

Wherein A, B, R₁, R₂, and R₃, are as defined earlier. Compound 2 can beprepared by variety of methods familiar to those skilled in art using abase like sodium hydroxide from commercially available sulfonyl chloride(1). Chlorination of 2 with reagents like thionyl chloride afforded 3.Compound 3 on treatment with ammonia under suitable conditions andappropriate solvents provided compound 4. Compound 4 on treatment withisocyanato derivative (5) under suitable conditions, in presence of baselike butyl lithium and appropriate solvents provided compound of formula6. Compound 6 was subjected to chlorination with suitable reagent undersuitable conditions, base and solvent followed by reaction withoptionally substituted amines to afford compounds of formula (I). Chiralseparation of the compounds of formula (I) can be achieved usingsuitable chiral columns via techniques like HPLC; or by using suitablechiral reagents, by a person skilled in the art.

The invention is further illustrated by the following non-limitingexamples which describe the preferred way of carrying out the presentinvention. These are provided without limiting the scope of the presentinvention in any way.

¹H NMR spectral data given in the examples (vide infra) are recordedusing a 400 MHz spectrometer (Bruker AVANCE-400) and reported in 6scale. Until and otherwise mentioned the solvent used for NMR is CDCl₃using TMS as the internal standard.

Example-1: Preparation ofN′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-4-methyl BenzeneSulfonimidamide Intermediate-1: Preparation 4-methylbenzenesulfinic Acid

Sodium sulfite (12.64 g, 100 mmol) was dissolved in water (50 mL) atroom temperature; it was heated to 65° C. temp. 10 M solution of NaOH(7.22 g, 181 mmol) was added drop wise. At the same timep-toluenesulfonyl chloride (15.3 g, 80 mmol) was added portion wise.After the addition the reaction mixture was heated to 70° C. for 3hours. After completion of starting material, hot solution was filteredand the filtrate was kept the fridge for 17 hours. Solid was ppt. out,filtered it. Then solid was dissolved in water (120 mL) and cooled to 0°C. temp., acidified with conc. HCl. stirred for 1 hour. and solid wasfiltered off, washed it with cold water (5 mL×3) and dried underdesiccator over P₂O₅ to yield 4-methylbenzenesulfinic acid (8.0 g, 51.2mmol, 63.8% yield)

¹H NMR (400 MHz, CDCl₃): δ=7.63 (d, 2H), 7.38 (d, 2H), 2.42 (s, 3H); MS(ESI): m/z (%)=154.4 (100%) (M−H)⁻.

Intermediate 2: Preparation of 4-methylbenzene-1-sulfinic Chloride

4-methylbenzenesulfinic acid (10.0 g, 64.0 mmol) was taken in ether (50mL), slurry was cooled to 0° C. and added thionyl chloride (18.69 ml,256 mmol) drop wise. After the addition was completed, ice bath wasremoved and reaction mixture was heated to 40° C. for 4 hours. Uponcompletion of starting material, reaction mixture was concentrated underreduced pressure to obtain crude 4-methylbenzene-1-sulfinic chloride(11.18 g, 64.0 mmol, 100% yield). It was directly used in the next stepwithout further purification.

Intermediate 3: Step 1: Preparation of 4-methylbenzenesulfinamide

4-methylbenzene-1-sulfinic chloride (11 g, 63.0 mmol) was dissolved inether (50 mL), it was cooled to 0° C. and ammonia gas was purged for 45min. Upon completion of starting material, reaction mixture wasconcentrated under reduced pressure. Then into it water was added, solidwas filtered off and washed with water. The obtained solid was driedunder reduced pressure in dessicator over P₂O₅ to yield4-methylbenzenesulfinamide (7.6 g, 49.0 mmol, 78% yield)

¹H NMR (400 MHz, CDCl₃): δ=7.65 (d, 2H), 7.33 (d, 2H), 4.29 (s, 2H),2.43 (s, 3H); MS (ESI): m/z (%)=155.33 (100%) (M+H)⁺

Intermediate 4: Preparation ofN-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfinamide

4-methylbenzenesulfinamide (1 eq.) was dissolved in THF (20 mL) under N₂atm. it was cooled to −78° C. and drop wise added n-butyl lithium (1.2eq), after the addition solution was stirred for 30 min. at −78° C.temp. Then bath was removed and reaction mixture was stirred for 30 min.at RT. Then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (1.2 eq.) wasadded drop wise at RT. Solid was ppt. then reaction mixture was furtherstirred for 4 h at RT. Upon completion of starting material, reactionmixture was concentrated under reduced pressure, resulting residue wastreated with water (30 mL) solid was collected by filtration, it waswashed with water and hexane, then dried under reduced pressure indessicator over P₂O₅ to yieldN-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfinamide.

Compound-1:N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide

N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfinamide(1.0 eq.) was taken in MeCN (10 mL) under N2 atm. Solid cyanamide (2.1eq.), potassium tert-butoxide (2 eq.) and N-Chlorosuccinimide (1.2 eq.)were added subsequently. The resulted suspension was stirred further for3 h at RT. Upon completion of starting material, reaction mixture wasconcentrated under reduced pressure. it was diluted with Ethyl Acetate(15 mL) and water, layers were separated, aq. layer was back extractedwith Ethyl Acetate (15 mL×4), all org. layer was combined and washedwith water (15 mL), brine (15 mL), dried it over Na₂SO₄ and conc. underreduced pressure at 45° C. to yield crude product, which was purified bypreparative HPLC to affordN′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide.

¹H NMR (400 MHz, DMSO-d₆): δ=7.91 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.27(d, J=8.0 Hz, 2H), 6.78 (s, 1H), 2.75-2.67 (m, 4H), 2.65-2.56 (m, 4H),2.34 (s, 3H), 1.92-1.83 (m, 4H); MS (ESI): m/z (%)=395.10 (100%) (M+H)⁺,393.15 (100%) (M+H)

Alternatively, the compounds of the general formula (I) can be preparedas described in schemes below along with suitablemodifications/variations which are well within the scope of a personskilled in the art.

Wherein PG is selected from silyl groups like tert-butyldiphenylsilyl,tert-butyldimethylsilyl, trimethylsilyl or 9-Fluorenylmethyl carbamate,FMOC (Fluorenylmethyloxycarbonyl), t-Butyl carbamate, BOC; Benzylcarbamate, Acetamide, Benzylamine, p-Toluenesulfonamide. A, B, R₁, R₂,and R₃, are as defined earlier. Compound 7 can be prepared by usingammonia from commercially available sulfonyl chloride (1). Protection ofamine group of 7 with suitable protecting groups like substituted silylchlorides afforded 8. Compound 8 on treatment with triphenyl phosphineand dichloroethane under suitable conditions and appropriate solventsprovide compound of compound 9. Compound 9 on treatment with isocyanatoderivative (5) under suitable conditions, base like butyl lithium andappropriate solvents yielded compound of formula 10. Compound 10 wassubjected to the deprotection with suitable reagent under suitableconditions, followed by reaction with optionally substituted halidesprovide compounds of formula (I). Chiral separation of the compounds offormula (I) can be achieved using suitable chiral columns via techniqueslike HPLC; or by using suitable chiral reagents, by a person skilled inthe art.

The invention is further illustrated by the following non-limitingexamples which describe the preferred way of carrying out the presentinvention. These are provided without limiting the scope of the presentinvention in any way.

Example-2: Preparation ofN′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-4-methyl BenzeneSulfonimidamide Intermediate-1: PreparationN-(tert-butyldimethylsilyl)-4-methylbenzenesulfonamide

4-methylbenzenesulfonamide (10.0 g, 58.4 mmol, 1 eq.) was taken in THF(50 mL), and added triethyl amine (17.41 mL, 128 mmol, 2.2 eq.) dropwise at 0° C., further a solution of tert-butylchlorodimethylsilane(11.0 g, 73 mmol, 1.25 eq.) in toluene (10 mL) was added. After theaddition completed, ice bath was removed and reaction mixture was heatedto 50° C. for 16 h. Upon completion of starting material, reactionmixture was concentrated under reduced pressure. Subsequently it wasdiluted with EA (100 mL) and water, layers were separated, aq. layer wasback extracted with EA (50 mL×4), all org. layer was combined and washedwith water (50 mL), brine (50 mL), dried over Na₂SO₄ and conc. underreduced pressure at 45° C. to yield crude product, which was purified bycolumn chromatography to affordN-(tert-butyldimethylsilyl)-4-methylbenzenesulfonamide (12 g, 72% yield)

¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 7.69 (d, 2H, J=6.4 Hz), 7.58 (s, 1H),7.36 (d, 2H, J=8.4 Hz), 2.37 (s, 3H), 0.86 (s, 9H), 0.08 (s, 6H); MS(ESI): m/z (%)=285.9 (80%) (M+H)⁺

Intermediate 2: Preparation ofN′-(tert-butyldimethylsilyl)-4-methylbenzenesulfonimidamide

A solution of triphenylphosphane (5.05 g, 19.2 mmol, 1.1 eq.) andhexachloro ethane (4.56 g, 19.2 mmol, 1.1 eq.) in chloroform (50 mL) washeated to 70° C. for 5 h. Reaction mixture was cooled to 0° C. and addedtriethy amine (2.66 g, 26.3 mmol, 1.5 eq.) further a solution ofN-(tert-butyldimethylsilyl)-4-methylbenzenesulfonamide (5.0 g, 17.51mmol, 1.0 eq.) in chloroform (10 mL) was added. After 20 minutes at 0°C., ammonia gas was purged. Reaction mixture was concentrated to yieldcrude product, which was purified by column chromatography to affordN′-(tert-butyldimethylsilyl)-4-methylbenzenesulfon-imidamide (3.2 g, 64%yield)

¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 7.54-7.73 (m, 2H), 7.30 (d, 2H, J=8Hz), 6.57 (s, 2H), 2.35 (s, 3H), 0.87 (s, 9H), 0.00 (s, 6H); MS (ESI):m/z (%)=284.9 (100%) (M+H)⁺.

Intermediate 3: Preparation ofN′-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide

To a solution ofN′-(tert-butyldimethylsilyl)-4-methylbenzenesulfon-imidamide (1.7 g,5.98 mmol, 1.0 eq.) in dry THF (25 mL) was added n-BuLi (2.87 mL, 2.5 M,7.17 mmol, 1.2 eq.) at −78° C. The reaction mixture was stirred at thistemperature for 0.5 h and at rt for 0.5 h.4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (1.19 g, 5.98 mmol, 1.0eq.) was added to the reaction mixture at room temperature (RT) andstirred for 2 h. Reaction mixture was cooled to 0° C. and quenched withNH₄Cl. It was diluted with EA (100 mL) and water, layers were separated,aq. layer was back extracted with EA (50 mL×4), all org. layer wascombined and washed with water (50 mL), brine (50 mL), dried it overNa2SO4 and conc. under reduced pressure at 45° C. to yield, crudeproduct, which was used for next step.

¹H NMR (DMSO-d₆, 400 MHz) δ ppm: 9.93 (s, 1H), 8.06 (s, 1H), 7.82 (d,2H, J=8 Hz), 7.37 (d, 2H, J=8 Hz), 6.90 (s, 1H), 2.78-2.67 (m, 4H),2.56-2.50 (m, 4H), 2.35 (s, 3H), 1.95-1.91 (m, 4H), 0.90 (s, 9H), 0.00(s, 6H); MS (ESI): m/z (%)=484.5 (100%) (M+H)⁺

Intermediate 4: Preparation ofN-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide

To a solution ofN′-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide(3.3 g, 6.82 mmol, 1.0 eq.) in dry THF (35 mL) was added HCl-dioxane(5.12 mL, 4 M, 7.17 mmol, 3 eq.) at 0° C. The reaction mixture wasstirred at this temperature for 0.5 h and at RT for 1 h. Reactionmixture was cooled to 0° C. and quenched with aq. ammonia and waster wasadded. This mixture was filtered and dried under vacuum to yieldN-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamideas white solid (2.2 g, Yield=87%)

¹H NMR (400 MHz, DMSO-d₆): δ=9.42 (s, 1H), 7.54 (d, J=7.6 Hz, 2H), 7.34(d, J=7.6 Hz, 2H), 6.92 (s, 1H), 6.2 (bs, 2H), 2.82-2.79 (m, 8H), 2.36(s, 3H), 1.82-1.72 (m, 4H); MS (ESI): m/z (%)=370.00 (100%) (M+H)⁺,368.05 (100%) (M−H)⁻

Compound-2N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzeneSulfonimidamide

To a solution ofN-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide(0.1 g, 0.27 mmol, 1.0 eq.) in DMF (1 mL) was added triethylamine (0.15mL, 1.08 mmol, 4 eq.) and CNBr (0.057 g, 0.54 mmol, 2.0 eq.) at rt. Thereaction mixture was stirred at room temperature for 18 h The crudeproduct was purified by preparative HPLC to affordN′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide (1.024 g, Yield=22%)

¹H NMR (400 MHz, DMSO-d₆): δ=7.91 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.27(d, J=8.0 Hz, 2H), 6.78 (s, 1H), 2.75-2.67 (m, 4H), 2.65-2.56 (m, 4H),2.34 (s, 3H), 1.92-1.83 (m, 4H); MS (ESI): m/z (%)=395.10 (100%) (M+H)⁺,393.15 (100%) (M+H)

Using appropriate starting materials and suitable modifications of theprocess described in Example 2, including suitable addition and/ordeletion of steps as may be necessary, well within the scope of a personskilled in the art, the following compounds were prepared in ananalogues manner.

Example-3N′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.74 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.24(d, J=8.0 Hz, 2H), 7.09 (t, J=8.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 2H), 3.11(sept, J=7.2 Hz, 2H), 2.33 (s, 3H), 1.08 (d, J=7.2 Hz, 12H); MS (ESI):m/z (%)=399.20 (100%) (M+H)⁺, 397.15 (100%) (M−H)⁻.

Example-4N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=9.42 (s, 1H), 7.54 (d, J=7.6 Hz, 2H), 7.34(d, J=7.6 Hz, 2H), 6.92 (s, 1H), 6.2 (bs, 2H), 2.82-2.79 (m, 8H), 2.36(s, 3H), 1.82-1.72 (m, 4H); MS (ESI): m/z (%)=370.00 (100%) (M+H)⁺,368.05 (100%) (M−H)⁻; IR (KBr): ν=3379, 3325, 3359, 3207, 2941, 2843,1651, 1585, 1448, 1375, 1321, 1269 cm⁻¹.

Example-5N-((2,6-diisopropylphenyl)carbamoyl)-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=9.69 (bs, 1H), 7.54 (bs, 2H), 7.35 (d,J=8.0 Hz, 2H), 7.19 (s, 1H), 7.08 (d, J=7.6 Hz, 2H), 6.23 (bs, 2H), 3.21(bs, 2H), 2.36 (s, 3H), 1.06 (d, J=6.8 Hz, 6H), 0.86 (d, J=6.8 Hz, 6H);MS (ESI): m/z (%)=374.10 (100%) (M+H)⁺, 372.25 (100%) (M−H)⁻; IR (KBr):ν=3338, 3198, 3064, 2966, 2928, 2868, 1705, 1639, 1593, 1462, 1442,1381, 1265, 1145 cm⁻¹.

Example-6N-((2,6-diisopropylphenyl)carbamoyl)-4-methyl-N′-(2,2,2-trifluoroethyl)benzenesulfonimi-damide

¹H NMR (400 MHz, DMSO-d₆): δ=8.5 (s, 1H), 8.35 (s, 1H), 7.81 (d, J=8.4Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.19-7.05 (m, 3H), 3.72 (bs, 2H), 3.08(bs, 2H), 2.38 (s, 3H), 1.1 (d, J=6.4 Hz, 12H); MS (ESI): m/z (%)=456.17(100%) (M+H)⁺; (KBr): ν=3396, 3142, 2958, 2866, 1616, 1483, 1274, 1242,1170, 1085, 996 cm⁻¹.

Example-7N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-N′-(2,2,2-trifluoroethyl)-benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.5 (bs, 1H), 8.47 (s, 1H), 7.77 (bs,2H),7.42 (d, J=8.0 Hz, 2H), 6.88 (s, 1H), 3.72 (bs, 2H), 2.79 (t, J=6.8Hz, 4H), 2.68 (bs, 4H), 2.39 (s, 3H), 1.9 (t, J=7.2 Hz, 4H); MS (ESI):m/z (%)=452.20 (100%) (M+H)⁺

Example-8N-((2,6-diisopropylphenyl)carbamoyl)-N′-methoxy-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=9.82 (bs, 1H), 9.55 (s, 1H), 7.61 (d, J=8.0Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.10 (d, J=7.2Hz, 2H), 3.51 (s, 3H), 3.20 (bs, 2H), 2.43 (s, 3H), 1.06 (s, 6H), 0.74(s, 6H); MS (ESI): m/z (%)=404.24 (100%) (M+H)⁺

Example-9N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N′-isopropyl-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=9.35 (s, 1H), 7.54 (bs, 2H),7.35 (d, J=8.0Hz, 2H), 6.93 (s, 1H), 6.81 (d, J=6.8 Hz, 1H), 3.67 (d, J=6.8 Hz, 1H),2.80-2.71 (m, 6H), 2.37 (s, 3H), 2.20-2.19 (m, 2H), 1.91-1.82 (m, 4H),1.06-1.01 (m, 6H); MS (ESI): m/z (%)=412.27 (100%) (M+H)⁺

Example-10N-((2,6-diisopropylphenyl)carbamoyl)-N′-isopropyl-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=9.56 (s, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.35(d, J=7.6 Hz, 2H), 7.23 (t, J=6.4 Hz, 1H), 7.09 (d, J=7.6 Hz, 2H), 6.77(d, J=8.0 Hz, 1H), 3.67 (d, J=7.2 Hz, 1H), 3.22 (bs, 2H), 2.36 (s, 3H),1.07 (bs, 12H), 0.73 (s, 6H); MS (ESI): m/z (%)=416.30 (100%) (M+H)⁺

Example-11N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N′-methoxy-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=9.9 (bs, 1H), 9.35 (s, 1H), 7.58 (d, J=8.4Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 6.95 (s, 1H), 3.52 (s, 3H), 2.73 (t,J=6.8 Hz, 4H), 2.39 (s, 3H), 2.53-2.22 (m, 4H), 1.85-1.66 (m, 4H); MS(ESI): m/z (%)=400.20 (100%) (M+H)⁺

Example 12N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N′,4-dimethylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.4 (bs, 1H), 7.73 (d, J=7.6 Hz, 2H),7.42-7.36 (m, 3H), 6.87 (s, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.70 (t, J=7.6Hz, 4H), 2.39 (s, 6H), 1.96 (quin, J=7.6 Hz, 4H); MS (ESI): m/z(%)=384.10 (100%) (M+H)⁺; IR (KBr): ν=3286, 3142, 2939, 2843, 1626,1521, 1460, 1442, 1427, 1276, 1238, 1120 cm⁻¹

Example-13N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-N′-(1H-pyrazol-5-yl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=12.09 (s, 1H), 9.33 (s, 1H), 7.64 (d, J=7.6Hz, 2H), 7.50 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 6.96 (s, 1H), 6.30 (s,1H), 2.76-2.67 (m, 6H), 2.39 (s, 3H), 2.21-2.17 (m, 2H), 1.87-1.84 (m,4H); MS (ESI): m/z (%)=436.15 (100%) (M+H)⁺

Example-14N′-(4-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=10.08 (bs, 1H), 8.35 (s, 1H), 7.71 (s, 2H),7.36 (d, J=7.2 Hz, 2H), 7.07 (s, 4H), 6.89 (s, 1H), 2.79 (s, 4H), 2.67(s, 4H), 2.35 (s, 4H), 1.95 (d, J=6.8 Hz, 4H); MS (ESI): m/z (%)=464.35(100%) (M+H)⁺

Example-15N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-N′-(pyridin-2-yl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=9.38 (bs, 1H), 8.23 (d, J=3.6 Hz, 1H), 7.87(d, J=6.8 Hz, 1H), 7.70 (d, J=7.6 Hz, 3H), 7.39 (d, J=8.4 Hz, 2H), 7.00(t, J=7.2 Hz, 2H), 2.80-2.73 (m, 6H), 2.39 (s, 3H), 2.24 (bs, 2H),1.88-1.70 (m, 4H); MS (ESI): m/z (%)=447.25 (100%) (M+H)⁺

Example-164-acetyl-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.1 (bs, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.87(d, J=8.4 Hz, 2H), 6.80 (s, 1H), 2.75-2.70 (m, 4H), 2.67-2.63 (m, 4H),2.61 (s, 3H), 1.93 (t, J=7.2 Hz, 4H); MS (ESI): m/z (%)=423.10 (100%)(M+H)⁺; IR (KBr): ν=3433, 2949, 2845, 2189, 1687, 1599, 1541, 1263,1199, 1118, 821 cm⁻¹.

Example-17N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.0 (bs, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.55(d, J=8.4 Hz, 2H), 6.79 (s, 1H), 5.16 (s, 1H), 2.75 (t, J=7.2 Hz, 4H),2.68-2.66 (m, 4H), 1.91 (t, J=7.2 Hz, 4H), 1.43 (s, 6H); MS (ESI): m/z(%)=439.15 (100%) (M+H)⁺.

Example-18N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-nitrobenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.48 (s, 1H), 8.37 (d, J=8.4 Hz, 2H), 8.17(d, J=8.0 Hz, 2H), 7.82 (t, J=8.4 Hz, 2H), 6.80 (s, 1H), 2.78-2.69 (m,4H), 2.68-2.57 (m, 4H), 1.98-1.81 (m, 4H); MS (ESI): m/z (%)=426.10(100%) (M+H)⁺, 448.09 (15%) (M+Na).

Example-19N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methoxybenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.93 (s, 1H), 7.70 (d, J=9.2 Hz, 2H), 7.01(d, J=8.8 Hz, 2H), 6.79 (s, 1H), 3.80 (s, 3H), 2.76 (t, J=7.6 Hz, 4H),2.70-2.56 (m, 4H), 1.93-1.85 (m, 4H); MS (ESI): m/z (%)=411.19 (100%)(M+H)⁺, 433.17 (90%) (M+Na).

Example-20N′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-4-methoxybenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.55 (d, J=8.8 Hz, 2H), 7.48-7.44 (m, 2H);7.13 (d, J=9.2 Hz, 2H), 3.83 (s, 3H), 3.06-3.00 (m, 1H), 2.21-2.14 (m,1H), 1.37 (d, J=6.4 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 0.944 (d, J=6.8 Hz,3H), 0.194 (d, J=6.4 Hz, 3H); MS (ESI): m/z (%)=415.20 (100%) (M+H)⁺,437.25 (10%) (M+Na); IR (KBr): ν=3464, 2972, 1595, 1525, 1410, 1267,1147, 1014, 844, 557 cm⁻¹

Example-21N′-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.03 (br s, 1H), 7.81-7.77 (m, 2H), 7.32(t, J=8.8 Hz, 2H), 6.79 (s, 1H), 2.73 (t, J=7.2 Hz, 4H), 2.64-2.59 (m,4H), 1.90-1.87 (m, 4H); MS (ESI): m/z (%)=399.10 (100%) (M+H)⁺

Example-22N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.01 (br s, 1H), 7.77-7.75 (m, 2H),7.49-7.46 (m, 3H), 6.79 (s, 1H), 2.76-2.72 (m, 4H), 2.67-2.60 (m, 4H),1.93-1.89 (m, 4H).

Example-23N-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)(p-tolyl)-16-sulfanylidene)-methanesulfonamide

¹H NMR (400 MHz, DMSO): δ=11.9 (bs, 1H), 7.8 (bs, 1H), 7.71 (d, J=8 Hz,2H), 7.25 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 2.84 (s, 3H), 2.73-2.84 (m,4H), 2.59-2.67 (m, 4H), 2.41 (s, 3H), 1.89-1.97 (m, 4H); MS (ESI): m/z(%)=448.35 (30%) (M+H)⁺; 465.3 (100%) (M+H₂O)⁺.

Example-24N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxypyridine-3-sulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.51-8.48 (m, 1H), 8.04 (br s, 1H),8.01-7.93 (m, 1H), 6.92 (d, J=9.2 Hz, 1H), 6.80 (s, 1H), 3.87 (s, 3H),2.81-2.59 (m, 8H), 1.91-1.84 (m, 4H); MS (ESI): m/z (%)=412.20 (100%)(M+H)⁺

Example-25N′-cyano-3-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.08 (br s, 1H), 7.49-7.47 (m, 1H),7.43-7.39 (m, 2H), 6.80 (s, 1H), 2.73 (d, J=7.2 Hz, 4H), 2.68-2.58 (m,4H), 2.28 (s, 3H), 1.93-1.88 (m, 4H); MS (ESI): m/z (%)=413.15 (100%)(M+H)⁺; IR (KBr): ν=3433, 3234, 2951, 2193, 1599, 1577, 1533, 1492 cm⁻¹.

Example-264-chloro-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.05 (br s, 1H), 7.74 (d, J=8.8 Hz, 2H),7.56 (d, J=8.8 Hz, 2H), 6.80 (s, 1H), 2.74 (t, J=7.2 Hz, 4H), 2.68-2.59(m, 4H), 1.93-1.87 (m, 4H); MS (ESI): m/z (%)=415.10 (100%) (M+H)⁺; IR(KBr): ν=3257, 2945, 2845, 2189, 1678, 1597, 1535 cm⁻¹.

Example-274-bromo-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.06 (br s, 1H), 7.71-7.66 (m, 4H), 6.80(s, 1H), 2.74 (t, J=7.2 Hz, 4H), 2.68-2.59 (m, 4H), 1.93-1.84 (m, 4H);MS (ESI): m/z (%)=459.15 (100%) (M)⁺; IR (KBr): ν=3433, 3236, 2945,2843, 2191, 1599, 1573, 1531 cm⁻¹

Example-284-(benzyloxy)-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.91 (s, 1H), 7.70-7.66 (m, 2H), 7.47-7.45(m, 2H), 7.42-7.38 (m, 2H), 7.36-7.32 (m, 2H), 7.10-7.05 (m, 3H), 6.79(s, 1H), 5.16 (s, 1H), 3.34-2.68 (m, 4H), 2.67-2.90 (m, 4H), 1.91-1.89(m, 4H); MS (ESI): m/z (%)=487.35 (100%) (M+H)⁺, 509.45 (30%) (M+NH₄)⁺;485.55 (100%) (M−1); IR (KBr): ν=3223, 2947, 2177, 1593, 1496, 1251,1114, 1095, 827. 698, 532 cm⁻¹

Example-29N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(trifluoromethyl)-benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆, D2O—X): δ=8.12 (br, s, 1H), 7.94 (d, J=8.4 Hz,2H), 7.88 (d, J=8.4 Hz, 2H), 6.80 (s, 1H), 2.75-2.72 (m, 4H), 2.68-2.55(m, 4H), 1.91-1.87 (m, 4H); MS (ESI): m/z (%)=449.10 (100%) (M+H)⁺,471.15 (30%) (M+Na)⁺, 447.30 (70%) (M−1)⁺; IR (KBr): ν=3433, 3248, 2195,1600, 1402, 1323, 1132, 1062, 827, 709 cm⁻¹.

Example-30N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-2-sulfonimidamide

¹H NMR (400 MHz, DMSO): δ=11.9 (bs, 1H), 8.60-8.61 (m, 1H), 8.15 (bs,1H), 7.86-7.97 (m, 1H), 7.47-7.50 (m, 1H), 7.47-7.49 (m, 1H), 6.79 (s,1H), 2.75-2.72 (m, 4H), 2.51-2.69 (m, 4H), 1.76-1.91 (m, 4H); MS (ESI):m/z (%)=382.10 (100%) (M+H)⁺; IR (KBr): ν=3431, 2951, 2187, 1616, 1510,1197 cm⁻¹

Example-31 Ethyl((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)(p-tolyl)-λ⁶-sulfaneylidene)-carbamate

¹H NMR (400 MHz, DMSO): δ=8.10 (bs, 1H), 7.76-7.78 (m, 2H), 7.31 (d,J=7.2 Hz, 2H), 6.85 (s, 1H), 3.85-3.87 (m, 2H), 2.75-2.78 (m, 4H),2.61-2.67 (m, 4H), 2.36 (s, 3H), 1.92-1.95 (m, 4H), 1.08 (t, J=7.2 Hz,3H); MS (ESI): m/z (%)=442.30 (100%) (M+H)⁺; IR (KBr): ν=3348, 2953,2926, 1656, 1460, 1257 cm⁻¹.

Example-32N-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)-(p-tolyl)-λ⁶-sulfaneylidene)-acetamide

¹H NMR (400 MHz, DMSO): δ=11.9 (bs, 1H), 7.80-8.00 (m, 2H), 7.41 (d, J=8Hz, 2H), 6.89 (s, 1H), 2.71-2.81 (m, 4H), 2.60-2.69 (m, 4H), 2.39 (s,3H), 1.91-1.98 (m, 7H); MS (ESI): m/z (%)=412.15 (100%) (M+H)⁺; IR(KBr): ν=3265, 2949, 2845, 1720, 1630, 1247 cm⁻¹.

Example-33N′-carbamoyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO): δ=8.60 (bs, 1H), 7.75-7.95 (m, 2H), 7.51 (d,j=8.4 Hz, 2H), 6.90 (s, 1H), 2.77-2.80 (m, 4H), 2.65-2.77 (m, 4H), 2.39(s, 3H), 1.91-2.00 (m, 4H); MS (ESI): m/z (%)=413.15 (100%) (M+H)⁺.

Example-34N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.0 (bs, 1H), 7.89 (s, 1H), 7.61-7.55 (m,2H), 7.41-7.37 (m, 1H), 6.79 (s, 1H), 5.19 (s, 1H), 2.76 (t, J=8.0 Hz,4H), 2.67 (quin, J=7.2 Hz, 4H), 1.90 (t, J=7.6 Hz, 4H), 1.44 (s, 6H); MS(ESI): m/z (%)=439.15 (100%) (M+H)⁺; IR (KBr): ν=3400, 3294, 3257, 2976,2845, 2196, 1593, 1523, 1288, 1224, 1192 cm⁻¹.

Example-35N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(3-hydroxyoxetan-3-yl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.0 (bs, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.70(d, J=8.4 Hz, 2H), 6.79 (s, 1H), 6.49 (s, 1H), 4.79 (d, J=6.8 Hz, 2H),4.71 (d, J=6.0 Hz, 2H), 2.76 (t, J=7.2 Hz, 4H), 2.67 (quin, J=7.2 Hz,4H), 1.91 (t, J=7.6 Hz, 4H); MS (ESI): m/z (%)=453.25 (100%) (M+H)⁺.

Example-36N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=9.4 (s, 1H), 8.1 (bs, 1H), 7.87 (s, 1H),7.03 (s, 1H), 6.82 (s, 1H), 5.34 (s, 1H), 4.97 (s, 1H), 2.82-2.73 (m,4H), 2.68-2.65 (m, 4H), 1.95 (s, 3H), 1.91 (t, J=7.6 Hz, 4H); MS (ESI):m/z (%)=411.13 (100%) (M+H)⁺, 409.08 (100%) (M−H); IR (KBr): ν=3433,3255, 2946, 2845, 21963, 1656, 1600, 1531, 1460, 1274 cm⁻¹.

Example-375-bromo-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.13 (bs, 1H), 7.24 (s, 1H), 7.20 (s, 1H),6.63 (s, 1H), 2.76 (bs, 4H), 2.68 (q, J=6.4 Hz, 4H), 1.93 (t, J=6.4 Hz,4H); MS (ESI): m/z (%)=466.10 (100%) (M+H)⁺, 465.30 (100%) (M−H); IR(KBr): ν=3433, 3244, 2955, 2922, 2202, 2183, 1595, 1533, 1460, 1402,1276 cm⁻¹.

Example-38N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methoxybenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.26 (bs, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.35(t, J=8.0 Hz, 1H), 7.28 (t, J=2.0 Hz, 1H), 7.07-7.05 (m, 1H), 6.80 (s,1H), 3.79 (s, 3H), 2.76 (t, J=7.6 Hz, 4H), 2.68-2.63 (m, 4H), 1.93 (qui,J=6.8 Hz, 4H); MS (ESI): m/z (%)=411.20 (100%) (M+H)⁺, 409.20 (100%)(M−H); IR (KBr): ν=3423, 3225, 2937, 2848, 2198, 2175, 1597, 1541, 1483,1460, 1427 cm⁻¹.

Example-39N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.10 (bs, 1H), 7.55 (s, 1H), 6.82 (s, 1H),6.79 (s, 1H), 5.03 (s, 1H), 2.77 (t, J=7.2 Hz, 4H), 2.68 (t, J=7.2 Hz,4H), 1.94 (qui, J=7.2 Hz, 4H), 1.38 (s, 6H); MS (ESI): m/z (%)=429.20(100%) (M+H)⁺, 427.30 (100%) (M−H); IR (KBr): ν=3389, 3138, 2949, 2843,2191, 1620, 1512, 1274, 1240, 1197, 1118 cm⁻¹.

Example-40N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.96 (bs, 1H), 7.23 (d, J=6.8 Hz, 2H), 6.94(d, J=9.2 Hz, 1H), 6.80 (s, 1H), 4.28 (s, 4H), 2.76 (t, J=7.2 Hz, 4H),2.69-2.61 (m, 4H), 1.94 (qui, J=7.2 Hz, 4H); MS (ESI): m/z (%)=439.10(100%) (M+H)⁺, 437.10 (100%) (M−H); IR (KBr): ν=3431, 3232, 2928, 2195,2179, 1595, 1537, 1496, 1458, 1421, 1128, 1151 cm⁻¹.

Example-41N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.95 (bs, 1H), 7.23 (d, J=4.0 Hz, 1H), 6.82(d, J=4.0 Hz, 1H), 6.81 (s, 1H), 5.63 (s, 2H), 2.77 (t, J=7.2 Hz, 4H),2.68-2.65 (m, 4H), 1.94 (qui, J=7.2 Hz, 4H), 1.49 (s, 6H); MS (ESI): m/z(%)=445.10 (100%) (M+H)⁺, 443.10 (100%) (M−H).

Example-42N′-cyano-2-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methylbenzene-sulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.06 (bs, 1H), 7.55 (d, J=5.2 Hz, 1H),7.32-7.30 (m, 1H), 7.16-7.12 (m, 1H), 6.80 (s, 1H), 2.76 (t, J=7.2 Hz,4H), 2.68-2.64 (m, 4H), 2.31 (s, 3H), 1.94 (qui, J=7.6 Hz, 4H); MS(ESI): m/z (%)=413.13 (100%) (M+H)⁺; IR (KBr): ν=3433, 3246, 2929, 2845,2196, 2179, 1595, 1573, 1531, 1492, 1460, 1251 cm⁻¹.

Example-43N′-cyano-3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.95 (s, 1H), 8.14 (S, 1H), 8.04 (s, 1H),7.92 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H),6.79 (s, 1H), 2.75 (t, J=6.8 Hz, 4H), 2.62 (t, J=6.8 Hz, 4H), 1.91(quin, J=6.8 Hz, 4H); MS (ESI): m/z (%)=547.05 (100%) (M+H)⁺, 545.10(100%) (M−H); IR (KBr): ν=3369, 2955, 2847, 2189, 1610, 1510, 1269, 1197cm⁻¹.

Example-44N′-cyano-3,5-difluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.20 (s, 1H), 7.49-7.44 (m, 1H), 7.39-7.34(m, 2H), 6.82 (S, 1H), 2.72 (t, J=7.2 Hz, 4H), 2.62 (quin, J=7.6 Hz,4H), 1.94 (t, J=7.2 Hz, 4H); MS (ESI): m/z (%)=417.05 (100%) (M+H)⁺,415.05 (100%) (M−H); IR (KBr): ν=3238, 3086, 2956, 2196, 2181, 1597,1537, 1444, 1278 cm⁻¹.

Example 45N′-cyano-2,4-difluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.05 (bs, 1H), 7.84-7.78 (m, 1H), 7.38-7.32(m, 1H), 7.20-7.15 (m, 1H), 6.80 (S, 1H), 2.76 (t, J=7.2 Hz, 4H),2.69-2.61 (m, 4H), 1.93 (quin, J=7.2 Hz, 4H); MS (ESI): m/z (%)=416.99(100%) (M+H)⁺; IR (KBr): ν=3433, 3255, 2947, 2845, 2195, 1602, 1525,1487, 1201 cm⁻¹.

Example-46N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(trifluoromethoxy)-benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.15 (bs, 1H), 7.78 (d, J=8.0 Hz, 1H),7.67-7.63 (m, 2H), 7.53 (d, J=8.0 Hz, 1H), 6.80 (S, 1H), 2.76 (t, J=7.2Hz, 4H), 2.64 (t, J=8.0 Hz, 4H), 1.91 (t, J=4.8 Hz, 4H); MS (ESI): m/z(%)=464.91 (100%) (M)⁺; IR (KBr): ν=3433, 2953, 2847, 2185, 1608, 1261,1207 cm⁻¹.

Example-47N′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.89 (s, 1H), 7.78 (S, 1H), 7.62 (d, J=7.6Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.12 (t, J=7.6Hz, 1H), 7.01 (d, J=7.6 Hz, 2H), 5.17 (s, 1H), 3.12 (bs, 2H), 1.43 (6,1H), 1.08 (d, J=6.8 Hz, 12H); MS (ESI): m/z (%)=442.97 (100%) (M+H)⁺; IR(KBr): ν=3385, 2964, 2868, 2181, 1608, 1475, 1384, 1207, 1128, 844 cm⁻¹.

Example-48N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-phenylmethanesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.87 (bs, 1H), 7.43-7.30 (m, 5H), 6.84 (S,1H), 4.66 (d, J=13.2 Hz, 1H), 4.57 (d, J=13.2 Hz, 1H), 2.81-2.72 (m,8H), 1.99 (quin, J=7.6 Hz, 4H); MS (ESI): m/z (%)=395.15 (100%) (M+H)⁺,417.14 (20%) (M+Na)⁺; IR (KBr): ν=3315, 2945, 2845, 2119, 1604, 1525,1290, 1234, 1203, 945, 694 cm⁻¹.

Example-49N-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(3-(2-hydroxypropan-2-yl)phenyl)(oxo)-16-sulfaneylidene)methanesulfonamide

¹H NMR (400 MHz, DMSO-d₆): δ=10.67 (s, 1H), 7.92 (s, 1H), 7.73 (m, 2H),7.59 (d, J=15.6 Hz, 1H), 7.47-7.43 (m, 4H), 7.26-7.22 (m, 1H), 7.11 (d,J=8.0 Hz, 2H), 3.04-2.97 (m, 2H), 1.04 (s, 12H); MS (ESI): m/z(%)=491.89 (50%) (M+H)⁺, 513.86 (100%) (M+Na), 489.95 (100%) (M−1).

Example-50N′-cyano-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.65 (d, J=8.4 Hz, 2H), 7.63 (s, 1H), 7.33(s, 1H), 7.28 (d, J=8.4 Hz, 2H), 3.09 (m, 4H), 2.67 (m, 4H), 2.35 (s,3H), 1.97 (m, 4H); MS (ESI): m/z (%)=395.2 (100%) (M+1); IR (KBr):ν=3362, 2960, 2847, 2206, 1593, 1519, 1421, 1280, 1182 cm⁻¹.

Example 51N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.01 (s, 1H), 7.72 (d, J=1.2 Hz, 1H), 7.43(d, J=2.0 Hz, 1H), 7.06 (d, J=4.8 Hz, 1H), 6.81 (s. 1H), 2.73 (m, 4H),2.64 (m, 4H), 1.90 (m, 4H); MS (ESI): m/z (%)=387 (M+1).

Example 52N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dimethoxybenzene-sulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.95 (s, 1H), 7.34 (d, J=2.0 Hz, 1H), 7.29(d, J=2.0 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 6.69 (s, 1H), 3.94 (s, 3H).3.80 (s, 3H), 2.73 (m, 4H), 2.64 (m, 4H), 2.09 (m, 4H); MS (ESI): m/z(%)=441.2 (100%) (M+1); IR (KBr): ν=−3423.76, 2939.6, 2191.21, 1595.18,1508.38, 1261.49, 941.29 cm⁻¹.

Example 53N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methylpyridine-2-sulfonimidamide

¹H NMR (400 MHz, DMSO): δ=8.10 (bs, 1H), 7.85-7.81 (m, 1H), 7.68-7.66(m, 1H), 7.34-7.36 (m, 1H), 6.79 (s, 1H), 2.75-2.70 (m, 4H), 2.68-2.55(m, 4H), 2.50 (s, 3H), 1.99-1.86 (m, 4H); MS (ESI): m/z (%)=396.30(100%) (M+H)⁺; IR (KBr): ν=3367, 2949, 2189, 1732, 1612, 1195 cm⁻¹.

Example 54N′,3-dicyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO): δ=8.20 (bs, 1H), 8.06-7.98 (m, 3H), 7.76-7.72(m, 1H), 6.81 (s, 1H), 2.76-2.50 (m, 8H), 1.93-1.88 (m, 4H); MS (ESI):m/z (%)=405.95 (100%) (M+H)⁺; IR (KBr): ν=3412, 2949, 2191, 1599, 1251,1205 cm⁻¹.

Example 55N′,4-dicyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO): δ=8.15 (bs, 1H), 8.00-7.97 (m, 2H), 7.89-7.88(m, 2H), 6.80 (s, 1H), 2.80-2.50 (m, 8H), 1.93-1.19 (m, 4H); MS (ESI):m/z (%)=406.10 (100%) (M+H)⁺; IR (KBr): ν=3433, 3246, 2196, 1597, 1246cm⁻¹.

Example 56N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-3-sulfonimidamide

¹H NMR (400 MHz, DMSO): δ=8.87 (d, J=2 Hz, 1H), 8.67-7.66 (m, 1H), 8.10(bs, 1H), 8.09-8.07 (m, 1H), 7.56-7.53 (m, 1H), 6.80 (s, 1H), 2.76-2.60(m, 8H), 1.91-1.87 (m, 4H); MS (ESI): m/z (%)=382.05 (100%) (M+H)⁺; IR(KBr): ν=3267, 2951, 2193, 1599, 1257, 1232 cm⁻¹.

Example 57N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-4-sulfonimidamide

¹H NMR (400 MHz, DMSO): δ=8.74-8.73 (m, 2H), 8.20 (bs, 1H), 7.66-7.64(m, 2H), 6.81 (s, 1H), 2.76-2.59 (m, 8H), 1.91-1.87 (m, 4H); MS (ESI):m/z (%)=382.13 (100%) (M+H)⁺; IR (KBr): ν=3236, 2951, 2181, 1739, 1599,1247 cm⁻¹.

Example 58N′-cyano-3-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.11 (s, 1H), 7.58 (d, J=6.4 Hz, 2H), 7.48(d, J=8.8 Hz, 1H), 7.37 (d, J=2.8 Hz, 1H), 6.80 (s, 1H), 2.82 (m, 4H),2.64 (m, 4H), 1.91 (m, 4H); MS (ESI): m/z (%)=397 (100%) (M−1).

Example 59N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)quinoline-8-sulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=9.02 (s, 1H), 8.64 (d, J=9.2 Hz, 1H), 8.46(d, J=8.0 Hz, 1H), 8.20 (d, J=7.2 Hz, 1H), 7.78 (m, 1H), 7.72 (d, J=7.6Hz, 1H), 7.12 (s, 1H), 3.23 (m, 1H), 2.91 (m, 4H), 2.75 (m, 4H), 2.01(m, 4H); MS (ESI): m/z (%)=432.13 (100%) (M+1).

Example 60N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-morpholinobenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.87 (s, 1H), 7.59 (d, J=9.2 Hz, 2H), 6.97(d, J=8.8 Hz, 2H), 6.79 (s, 1H), 3.73 (t, J=4.8 Hz, 4H), 3.20 (t, J=4.8Hz, 4H), 2.85 (m, 4H), 2.65 (m, 4H), 1.91 (m, 4H); MS (ESI): m/z(%)=466.12 (100%) (M+1); IR (KBr): ν=3442, 2949, 2177, 1593, 1504, 1379,1240, 1190, 927 cm⁻¹.

Example 61N-(3-(N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)phenyl) acetamide

¹H NMR (400 MHz, DMSO-d₆): δ=10.16 (s, 1H), 7.96 (s, 2H), 7.76 (s, 1H),7.39 (d, J=2.0 Hz, 2H), 6.79 (s, 1H), 2.85 (m, 4H), 2.55 (m, 4H), 2.05(s, 3H), 1.85 (m, 4H); MS (ESI): m/z (%)=435.9 (100%) (M−1); IR (KBr):ν=3433, 2918, 2173, 1701, 1599, 1545, 1384, 1215, 1163, 1126, 840 cm⁻¹.

Example 62N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-morpholinobenzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.0 (s, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.20(d, J=8.0 Hz, 2H), 7.07 (d, J=1.60 Hz, 1H), 6.80 (s, 1H), 3.75 (t, J=4.8Hz, 4H), 3.12 (t, J=4.8 Hz, 4H), 2.74 (m, 4H), 2.71 (m, 4H), 1.95 (m,4H); MS (ESI): m/z (%)=465.98 (100%) (M+1); IR (KBr): ν=3433, 3225,2955, 2195, 1595, 1539, 1485, 1379, 1280, 1120, 937 cm⁻¹

Example 63N′-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO): δ=8.13 (dd, J=2.4 Hz, J=7.6 Hz, 1H), 8.00 (bs,1H), 7.68-7.64 (m, 1H), 7.24-7.19 (m, 2H), 6.79 (s, 1H), 2.76-2.60 (m,8H), 1.95-1.85 (m, 4H), 1.50 (s, 3H), 1.48 (s, 3H); MS (ESI): m/z(%)=456.88 (100%) (M+H)⁺; IR (KBr): ν=3369, 2953, 2185, 1614, 1215 cm-1.

Example 64N′-cyano-2-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)benzenesulfonimidamide

¹H NMR (400 MHz, DMSO): δ=8.10 (bs, 1H), 7.88 (dd, J=2.4 Hz, J=7.2 Hz,1H), 7.56-7.55 (m, 1H), 7.19-7.15 (m, 1H), 6.80 (s, 1H), 5.22 (s, 1H),2.76-2.61 (m, 8H), 1.99-1.87 (m, 4H), 1.42 (s, 6H); MS (ESI): m/z(%)=456.90 (100%) (M+H)⁺; IR (KBr): ν=3412, 2949, 2196, 1595, 1195 cm⁻¹.

Example 65N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)pyridine-3-sulfonimidamide

¹H NMR (400 MHz, DMSO): δ=8.75-8.72 (m, 2H), 8.22-8.14 (m, 2H), 6.80 (s,1H), 5.43 (s, 1H), 2.90-2.60 (m, 8H), 1.99-1.76 (m, 4H), 1.48 (s, 3H),1.47 (s, 3H); MS (ESI): m/z (%)=439.83 (100%) (M+H)⁺.

Example 66N′-cyano-1-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-methanesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=7.94 (bs, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.54(d, J=8.0 Hz, 2H), 6.84 (S, 1H), 4.78 (d, J=13.2 Hz, 1H), 4.68 (d,J=12.8 Hz, 1H), 2.79 (t, J=7.2 Hz, 4H), 2.73 (t, J=7.2 Hz, 4H), 1.97(quin, J=7.2 Hz, 4H); MS (ESI): m/z (%)=420.17 (100%) (M+H)⁺, 442.15(20%) (M+Na)⁺; IR (KBr): ν=3290, 2951, 2850, 2229, 2189, 1720, 1602,1529, 1460, 1286, 1228, 1161 cm⁻¹.

Example 671-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.2 (bs, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.58(d, J=7.6 Hz, 2H), 7.06 (S, 2H), 6.89 (S, 1H), 4.89 (d, J=13.2 Hz, 1H),4.75 (d, J=13.2 Hz, 1H), 2.80 (t, J=7.2 Hz, 4H), 2.67 (t, J=7.2 Hz, 4H),1.96 (t, J=7.2 Hz, 4H); MS (ESI): m/z (%)=395.15 (50%) (M+H)⁺, 393.04(100%) (M−H)⁺; IR (KBr): ν=3275, 3176, 2949, 2843, 2231, 1618, 1531,1460, 1288, 1246, 1151, 829 cm⁻¹.

Example b ϵN′-cyano-3-(2-hydroxypropan-2-yl)-N-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carba-moyl)-benzenesulfonimidamide

¹H NMR (400 MHz, DMSO-d₆): δ=8.89 (s, 1H), 7.92 (S, 1H), 7.60 (q, J=7.6Hz, 2H), 7.41 (t, J=7.6 Hz, 1H), 7.00 (s, 1H), 5.21 (s, 1H), 2.82 (t,J=4.4 Hz, 2H), 2.82 (t, J=7.6 Hz, 2H), 2.77-2.67 (m, 4H), 1.85 (t, J=6.0Hz, 2H), 1.43 (s, 6H); MS (ESI): m/z (%)=453.35 (100%) (M+H)⁺, 475.35(50%) (M+Na)⁺; IR (KBr): ν=3421, 2964, 2926, 2181, 1672, 1651, 1614,1508, 1460, 1419, 1251, 1190 cm⁻¹.

Biological Activity: In-Vitro Assays:

THP1 (Tamm-Horsfall Protein 1) monocytes were differentiated with PMA(Phorbol 12-myristate 13-acetate) (100 ng/ml) and incubated at 37° C.for 20 h in presence of 5% CO₂. 2×10⁵ differentiated cells were platedper well of 96 well tissue culture plates. The cells were primed using500 ng/ml Lipopolysaccharide and incubating for 4 hrs under the samecondition. The cells were then treated with various concentrations ofthe compounds for 30 min followed by treatment with 5 mM ATP for 1 hr.The supernatants were collected and analysed by IL-1b (Mabtech Cat#3415-1H-20) or TNF-a (Mabtech; Cat #3510-1H-20) detection kit. The datawere analyzed using GraphPad Prism V7.0. Dose Response Curve (DRC) wasconstructed to determine the IC₅₀ value by fitting percentage cellsurvival data to the GraphPad Prism using nonlinear regression analysis.The in vitro IL-1β inhibitory activity (IC₅₀) for representativecompounds is listed in Table 1:

TABLE 1 Compound IC₅₀ (nM) Example 1 6.6 Example 17 12 Example 18 15Example 19 23 Example 21 62 Example 22 13 Example 24 34 Example 25 5Example 26 23 Example 27 27 Example 29 32 Example 30 28 Example 34 3Example 35 13 Example 36 32 Example 37 5.6 Example 38 17 Example 39 3.3Example 40 13 Example 41 4.8 Example 42 2.4 Example 43 27 Example 44 63Example 45 23 Example 46 — Example 48 3.5 Example 51 19 Example 52 4.4Example 53 45 Example 54 12 Example 55 27 Example 56 43 Example 58 38Example 63 7.8 Example 64 7.7 Example 65 1.26 Example 66 4

In Vivo Efficacy Studies:

Demonstration of in vivo efficacy of test compounds in rats mice, oralroutes of administration.

Animals

All the animal experiments were carried out in female rats and mice,bred in-house. Animals were housed in groups of 6 animals per cage, fora week, in order to habituate them to vivarium conditions (25±4° C.,60-65% relative humidity, 12: 12 h light: dark cycle, with lights on at7.30 am). All the animal experiments were carried out according to theinternationally valid guidelines following approval by the ‘ZydusResearch Center animal ethical committee’.

In-Vivo LPS and ATP Induced IL-1β Assay:

Female C57 mice (6-8 weeks) received intraperitoneal injection of 50μg/mouse of lipopolysaccharide (LPS) in PBS. Animals were treatedimmediately with the test compounds or the vehicle. After 2 h of LPSinjection, animals were administered with ATP at 12.5 mg/mouse dissolvedin PBS via intraperitoneal route. After 30 minutes of ATP injection,serum was collected for IL-1β estimation by ELISA.

The novel compounds of the present invention can be formulated intosuitable pharmaceutically acceptable compositions by combining withsuitable excipients by techniques and processes and concentrations asare well known.

The compounds of formula (I) or pharmaceutical compositions containingthem are useful as a medicament for the inhibition of NLRP3 activity andsuitable for humans and other warm blooded animals, and may beadministered either by oral, topical or parenteral administration. Thus,a pharmaceutical composition comprising the compounds of the presentinvention may comprise a suitable binder, suitable bulking agent &/ordiluent and any other suitable agents as may be necessary. Optionally,the pharmaceutical composition may be suitably coated with suitablecoating agents.

The compounds of the present invention (I) are NLRP3 inhibitors and areuseful in the treatment of disease states mediated by NLRP3, preferablydiseases or conditions in which interleukin 1 β activity in whichinterleukin 1β activity and interleukin-18 (IL-18) are implicated andrelated disorders.

The quantity of active component, that is, the compounds of Formula (I)according to this invention, in the pharmaceutical composition and unitdosage form thereof may be varied or adjusted widely depending upon theparticular application method, the potency of the particular compoundand the desired concentration. Generally, the quantity of activecomponent will range between 0.5% to 90% by weight of the composition.

The compounds of the present invention, formula (I), may be used aloneor in any combination with one or more other therapeutic agents which askilled medical practitioner can easily identify. Such other therapeuticagent may be selected depending on the type of disease being treated,the severity, other medications being taken by the patients etc. Thusfor example, for treatment of rheumatoid arthritis, one or more DMARDsmay be used in combination with the compounds of the present invention.

In one of the embodiments compound of formula (I) of the presentinvention may be used in combination with one or more suitablepharmaceutically active agents selected from following therapeuticagents in any combination. Inhibitors of interleukin-1β (e.g.rilonacept, canakinumab, and anakinra); immune-suppressants (e.g.,Methotrexate, mercaptopurine, cyclophosphamide), metabolic disordersdrugs, glucocorticoids, non-steroidal anti-inflammatory drugs, Cox-2specific inhibitors, TNF-α binding proteins (eg., Infliximab,etanercept), interferon-13, interferon, interleukin-2, antihistamines,beta-agonist, BTK inhibitors, anticolinergics, anti-cancer agents ortheir suitable pharmaceutically acceptable salts. Further examples foruse in combination with Non-Alcoholic Steato-Hepatitis (NASH) andfibrosis drugs, anticancer antibiotics, hormones, Aromatase inhibitors,antibodies, cytokines, vaccines, drug conjugates, inhibitors ofmitogen-activated protein kinase signaling (ex: BAY 43-9006), Sykinhibitors, mTOR inhibitors, antibodies (Rituxan), and BCR/ABLantagonist.

1. Compound having the structure of general formula (I)

wherein ‘A’ is selected from unsubstituted or substituted (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₃-C₆)cycloalkyl, aryl, heteroaryl and heterocyclylgroups having optionally one or more than one heteroatoms; ‘B’ isselected from optionally substituted (C₃-C₆)cycloalkyl, aryl, heteroaryland heterocyclyl or the following ring system

wherein X, Y, Z at each occurrence is independently selected from C, N,S, SO₂, and O, which may be optionally substituted; R¹ at eachoccurrence independently represents hydrogen, halogen, haloalkyl, cyano,optionally substituted groups selected from (C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, aryl, heteroaryl,heterocyclyl, benzyl, mercapto alkyl, sulfur and its oxidized form; whenA represents ring, R¹ may represent one or more substituents selectedfrom hydrogen, halogen, haloalkyl, cyano, optionally substituted groupsselected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkoxy,(C₃-C₆)cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, thiol,mercapto alkyl, sulfur and its oxidized forms, C₁-C₆(thio-alkoxy),bridged or spiro ring system having optionally one or more than oneheteroatoms; R² at each occurrence independently represents hydrogen,halide, cyano, optionally substituted groups selected from (C₁-C₆)alkyl,(C₂-C₆) alkenyl, (C₁-C₆)alkoxy (C₃-C₆)cycloalkyl, benzyl, aryl,heteroaryl, heterocyclyl, thiol, thioalkyl, thio-alkoxy sulfur and itsoxidized forms, bridged or spiro ring system having optionally one ormore than one heteroatoms; R³ at each occurrence independentlyrepresents hydroxyl, halogen, nitro, cyano, optionally substitutedgroups selected from (C₁-C₁₀)alkyl, (C₁-C₁₀)alkoxy, (C₃-C₁₀)cycloalkyl,(C₂-C₁₀) alkenyl, (C₂-C₁₀)alkynyl, SO₂(C₁-C₆)alkyl, benzyl, aryl,heteroaryl, heterocyclyl, thiol, thioalkyl, thio-alkoxy, (sulfur and itsoxidized forms), or R³ and A together with the atom to which they areattached may form a optionally substituted 5 to 7 membered heterocyclicring system having optionally one or more than one heteroatoms; ‘m’represents an integer from 1-5; Each of R₄, R₅, R₆, R₇, R₈, and R₉ ateach occurrence are independently selected from hydrogen, halogen,cyano, amide, sulphonamide, acyl, hydroxyl, optionally substitutedgroups selected from (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₃-C₆)cycloalkyl,(C₁-C₆)alkoxy; Alternatively each of R₅ and R₆, R₇ and R₈ or R₈ and R₉wherever possible, together may form a 4 to 7 membered saturated orpartially saturated ring containing from 0-2 additional heteroatomsselected from the group consisting of N, O, and S(O)_(p); p=1-2.
 2. Thecompound as claimed in claim 1 wherein heterocyclyl is selected fromsingle or fused mono, bi or tricyclic aromatic or non-aromatic groupscontaining one or more hetero atoms selected from O, N or S.
 3. Thecompound as claimed in claim 2, wherein the heterocyclic group isselected from tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane,morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane,imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran,dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane,oxathiane, thiomorpholine.
 4. The compound as claimed in claim 1,wherein heteroaryl group is selected from pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl,pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl,benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl,indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl,indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl,phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl,quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl,benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl,dibenzofuranyl.
 5. The compound as claimed in claim 1, wherein thesubstitutions are selected from hydrogen, hydroxy, cyano, halo,haloalkyl, haloalkyloxy, alkylthio (C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₃-C₁₀)cycloalkyl, C₁-C₆ alkoxy, —COR_(D), —CSR₁₀,C(O)OR₁₀, C(O)—R₁₀, —C(O)—NR₁₁R₁₂, —C(S)—NR₁₁R₁₂, —SO₂R₁₀ group, whereinR₁₀ is independently selected from hydrogen, optionally substitutedgroup selected from (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₃-C₇)cycloalkyl, aryl, heteroaryl, heterocyclyl group; R₁₁ and R₁₂ areindependently selected from hydrogen, optionally substituted groupselected from (C₁-C₆)alkyl, (C₁-C₆)alkoxy, aryl or benzyl group.
 6. Acompound as claimed in claim 1 selected from the group comprising of:N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;N′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-4-methylbenzenesulfonimidamide;N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;N-((2,6-diisopropylphenyl)carbamoyl)-4-methylbenzenesulfonimidamide;N-((2,6-diisopropylphenyl)carbamoyl)-4-methyl-N′-(2,2,2-trifluoroethyl)benzenesulfonimi-damide;N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-N′-(2,2,2-trifluoroethyl)-benzenesulfonimidamide;N-((2,6-diisopropylphenyl)carbamoyl)-N′-methoxy-4-methylbenzenesulfonimidamide;N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N′-isopropyl-4-methylbenzenesulfonimidamide;N-((2,6-diisopropylphenyl)carbamoyl)-N′-isopropyl-4-methylbenzenesulfonimidamide;N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N′-methoxy-4-methylbenzenesulfo-nimidamide;N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-N′,4-dimethylbenzenesulfonimidamide;N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-N′-(1H-pyrazol-5-yl)benzenesulfonimidamide;N′-(4-fluorophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methyl-N′-(pyridin-2-yl)benzenesulfonimidamide;4-acetyl-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-nitrobenzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methoxybenzenesulfo-nimidamide;N′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-4-methoxybenzenesulfonimidamide;N′-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;N-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)(p-tolyl)-16-sulfanylidene)-methanesulfonamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methoxypyridine-3-sulfonimidamide;N′-cyano-3-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;4-chloro-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;4-bromo-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;4-(benzyloxy)-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(trifluoromethyl)-benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-2-sulfonimidamide;Ethyl((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)(p-tolyl)-λ⁶-sulfaneylidene)-carbamate;N-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(oxo)-(p-tolyl)-λ⁶-sulfaneylidene)-acetamide;N′-carbamoyl-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-methylbenzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(3-hydroxyoxetan-3-yl)benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(prop-1-en-2-yl)furan-2-sulfonimidamide;5-bromo-N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methoxybenzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamideN′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide;N′-cyano-2-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-methylbenzene-sulfonimidamide;N′-cyano-3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamideN′-cyano-3,5-difluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;N′-cyano-2,4-difluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(trifluoromethoxy)-benzenesulfonimidamide;N′-cyano-N-((2,6-diisopropylphenyl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-phenylmethanesulfonimidamide;N-((3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)ureido)(3-(2-hydroxypropan-2-yl)phenyl)(oxo)-16-sulfaneylidene)methanesulfonamide;N′-cyano-N-((1,2,3,6,7,8-hexahydro-as-indacen-4-yl)carbamoyl)-4-methylbenzenesulfo-nimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)thiophene-2-sulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3,4-dimethoxybenzene-sulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methylpyridine-2-sulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-6-methylpyridine-2-sulfonimidamide;N′,3-dicyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;N′,4-dicyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzene-sulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)pyridine-4-sulfonimidamide;N′-cyano-3-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)quinoline-8-sulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-morpholinobenzenesulfonimidamide;N-(3-(N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)sulfamidimidoyl)phenyl) acetamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-morpholinobenzenesulfonimidamide;N′-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide;N′-cyano-2-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)benzenesulfonimidamide;N′-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)pyridine-3-sulfonimidamide;N′-cyano-1-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-methanesulfonimidamide;1-(4-cyanophenyl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)methanesulfonimidamide;N′-cyano-3-(2-hydroxypropan-2-yl)-N-((3-oxo-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carba-moyl)-benzenesulfonimidamide.7. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of Formula (I) as claimed in any of the precedingclaims and optionally one or more pharmaceutically acceptable carriers,diluents or excipients.
 8. A method of treating diseases medicated bythe NLRP3 modulators as well as treatment of diseases or conditions inwhich interleukin 1β activity and interleukin-18 (IL-18) are implicatedwhich comprising administering to a patient in need thereof an effectiveamount of a compound of Formula (I) as claimed in any of the precedingclaims or its suitable pharmaceutical composition.
 9. The use ofcompounds of formula (I) or its pharmaceutical compositions as claimedin any of the preceding claim suitable for treatment of diseases whereinthe NLRP3 modulator has a pathophysiological function.
 10. Thepharmaceutical composition as claimed in claims 1 and 6 in combinationwith one or more suitable pharmaceutically active agents selected fromInhibitors of interleukin-1β; immune-suppressants; metabolic disordersdrugs, glucocorticoids, non-steroidal anti-inflammatory drugs, COX-2specific inhibitors, TNF-α binding proteins, interferon-13, interferon,interleukin-2, antihistamines, beta-agonist, BTK inhibitors,anticolinergics, anti-cancer agents or their suitable pharmaceuticallyacceptable salts, Non-Alcoholic Steato-Hepatitis (NASH) and fibrosisdrugs, anticancer drugs, antibiotics, hormones, aromatase inhibitors,inhibitors of mitogen-activated protein kinase signaling, Sykinhibitors, mTOR inhibitors, and BCR/ABL antagonists.
 11. Intermediatecompound for the preparation of compound of formula 1 as claimed inclaim 1

wherein PG is selected from silyl groups like tert-butyldiphenylsilyl,tert-butyldimethylsilyl, trimethylsilyl or 9-Fluorenylmethyl carbamate,FMOC (Fluorenylmethyloxycarbonyl), t-Butyl carbamate, BOC; Benzylcarbamate, Acetamide, Benzylamine, p-Toluenesulfonamide; A, ring B, R₁and (R₂) are as defined in claim 1.